Cell-free DNA (cfDNA) may allow for minimally invasive identification of biologically relevant genomic alterations and genetically distinct tumor subclones. Although existing biomarkers may detect localized prostate cancer, additional strategies interrogating genomic heterogeneity are necessary for identifying and monitoring aggressive disease. In this study, we aimed to evaluate whether circulating tumor DNA can detect genomic alterations present in multiple regions of localized prostate tumor tissue. METHODS: Low-pass whole-genome and targeted sequencing with a machine-learning guided 2.5-Mb targeted panel were used to identify single nucleotide variants, small insertions and deletions (indels), and copy-number alterations in cfDNA. The majority of this study focuses on the subset of 21 patients with localized disease, although 45 total individuals were evaluated, including 15 healthy controls and nine men with metastatic castration-resistant prostate cancer. Plasma cfDNA was barcoded with duplex unique molecular identifiers. For localized cases, matched tumor tissue was collected from multiple regions (one to nine samples per patient) for comparison. RESULTS: Somatic tumor variants present in heterogeneous tumor foci from patients with localized disease were detected in cfDNA, and cfDNA mutational burden was found to track with disease severity. Somatic tissue alterations were identified in cfDNA, including nonsynonymous variants in FOXA1, PTEN, MED12, and ATM. Detection of these overlapping variants was associated with seminal vesicle invasion (P = .019) and with the number of variants initially found in the matched tumor tissue samples (P = .0005). CONCLUSION: Our findings demonstrate the potential of targeted cfDNA sequencing to detect somatic tissue alterations in heterogeneous, localized prostate cancer, especially in a setting where matched tumor tissue may be unavailable (ie, active surveillance or treatment monitoring).
Cell-free DNA (cfDNA) may allow for minimally invasive identification of biologically relevant genomic alterations and genetically distinct tumor subclones. Although existing biomarkers may detect localized prostate cancer, additional strategies interrogating genomic heterogeneity are necessary for identifying and monitoring aggressive disease. In this study, we aimed to evaluate whether circulating tumor DNA can detect genomic alterations present in multiple regions of localized prostate tumor tissue. METHODS: Low-pass whole-genome and targeted sequencing with a machine-learning guided 2.5-Mb targeted panel were used to identify single nucleotide variants, small insertions and deletions (indels), and copy-number alterations in cfDNA. The majority of this study focuses on the subset of 21 patients with localized disease, although 45 total individuals were evaluated, including 15 healthy controls and nine men with metastatic castration-resistant prostate cancer. Plasma cfDNA was barcoded with duplex unique molecular identifiers. For localized cases, matched tumor tissue was collected from multiple regions (one to nine samples per patient) for comparison. RESULTS: Somatic tumor variants present in heterogeneous tumor foci from patients with localized disease were detected in cfDNA, and cfDNA mutational burden was found to track with disease severity. Somatic tissue alterations were identified in cfDNA, including nonsynonymous variants in FOXA1, PTEN, MED12, and ATM. Detection of these overlapping variants was associated with seminal vesicle invasion (P = .019) and with the number of variants initially found in the matched tumor tissue samples (P = .0005). CONCLUSION: Our findings demonstrate the potential of targeted cfDNA sequencing to detect somatic tissue alterations in heterogeneous, localized prostate cancer, especially in a setting where matched tumor tissue may be unavailable (ie, active surveillance or treatment monitoring).
Authors: Paul C Boutros; Michael Fraser; Nicholas J Harding; Richard de Borja; Dominique Trudel; Emilie Lalonde; Alice Meng; Pablo H Hennings-Yeomans; Andrew McPherson; Veronica Y Sabelnykova; Amin Zia; Natalie S Fox; Julie Livingstone; Yu-Jia Shiah; Jianxin Wang; Timothy A Beck; Cherry L Have; Taryne Chong; Michelle Sam; Jeremy Johns; Lee Timms; Nicholas Buchner; Ada Wong; John D Watson; Trent T Simmons; Christine P'ng; Gaetano Zafarana; Francis Nguyen; Xuemei Luo; Kenneth C Chu; Stephenie D Prokopec; Jenna Sykes; Alan Dal Pra; Alejandro Berlin; Andrew Brown; Michelle A Chan-Seng-Yue; Fouad Yousif; Robert E Denroche; Lauren C Chong; Gregory M Chen; Esther Jung; Clement Fung; Maud H W Starmans; Hanbo Chen; Shaylan K Govind; James Hawley; Alister D'Costa; Melania Pintilie; Daryl Waggott; Faraz Hach; Philippe Lambin; Lakshmi B Muthuswamy; Colin Cooper; Rosalind Eeles; David Neal; Bernard Tetu; Cenk Sahinalp; Lincoln D Stein; Neil Fleshner; Sohrab P Shah; Colin C Collins; Thomas J Hudson; John D McPherson; Theodorus van der Kwast; Robert G Bristow Journal: Nat Genet Date: 2015-05-25 Impact factor: 38.330
Authors: Michael Fraser; Veronica Y Sabelnykova; Takafumi N Yamaguchi; Lawrence E Heisler; Julie Livingstone; Vincent Huang; Yu-Jia Shiah; Fouad Yousif; Xihui Lin; Andre P Masella; Natalie S Fox; Michael Xie; Stephenie D Prokopec; Alejandro Berlin; Emilie Lalonde; Musaddeque Ahmed; Dominique Trudel; Xuemei Luo; Timothy A Beck; Alice Meng; Junyan Zhang; Alister D'Costa; Robert E Denroche; Haiying Kong; Shadrielle Melijah G Espiritu; Melvin L K Chua; Ada Wong; Taryne Chong; Michelle Sam; Jeremy Johns; Lee Timms; Nicholas B Buchner; Michèle Orain; Valérie Picard; Helène Hovington; Alexander Murison; Ken Kron; Nicholas J Harding; Christine P'ng; Kathleen E Houlahan; Kenneth C Chu; Bryan Lo; Francis Nguyen; Constance H Li; Ren X Sun; Richard de Borja; Christopher I Cooper; Julia F Hopkins; Shaylan K Govind; Clement Fung; Daryl Waggott; Jeffrey Green; Syed Haider; Michelle A Chan-Seng-Yue; Esther Jung; Zhiyuan Wang; Alain Bergeron; Alan Dal Pra; Louis Lacombe; Colin C Collins; Cenk Sahinalp; Mathieu Lupien; Neil E Fleshner; Housheng H He; Yves Fradet; Bernard Tetu; Theodorus van der Kwast; John D McPherson; Robert G Bristow; Paul C Boutros Journal: Nature Date: 2017-01-09 Impact factor: 49.962
Authors: Colin S Cooper; Rosalind Eeles; David C Wedge; Peter Van Loo; Anne Y Warren; Christopher S Foster; Hayley C Whitaker; Ultan McDermott; Daniel S Brewer; David E Neal; Gunes Gundem; Ludmil B Alexandrov; Barbara Kremeyer; Adam Butler; Andrew G Lynch; Niedzica Camacho; Charlie E Massie; Jonathan Kay; Hayley J Luxton; Sandra Edwards; ZSofia Kote-Jarai; Nening Dennis; Sue Merson; Daniel Leongamornlert; Jorge Zamora; Cathy Corbishley; Sarah Thomas; Serena Nik-Zainal; Sarah O'Meara; Lucy Matthews; Jeremy Clark; Rachel Hurst; Richard Mithen; Robert G Bristow; Paul C Boutros; Michael Fraser; Susanna Cooke; Keiran Raine; David Jones; Andrew Menzies; Lucy Stebbings; Jon Hinton; Jon Teague; Stuart McLaren; Laura Mudie; Claire Hardy; Elizabeth Anderson; Olivia Joseph; Victoria Goody; Ben Robinson; Mark Maddison; Stephen Gamble; Christopher Greenman; Dan Berney; Steven Hazell; Naomi Livni; Cyril Fisher; Christopher Ogden; Pardeep Kumar; Alan Thompson; Christopher Woodhouse; David Nicol; Erik Mayer; Tim Dudderidge; Nimish C Shah; Vincent Gnanapragasam; Thierry Voet; Peter Campbell; Andrew Futreal; Douglas Easton; Michael R Stratton Journal: Nat Genet Date: 2015-03-02 Impact factor: 38.330
Authors: Zachary R Chalmers; Caitlin F Connelly; David Fabrizio; Laurie Gay; Siraj M Ali; Riley Ennis; Alexa Schrock; Brittany Campbell; Adam Shlien; Juliann Chmielecki; Franklin Huang; Yuting He; James Sun; Uri Tabori; Mark Kennedy; Daniel S Lieber; Steven Roels; Jared White; Geoffrey A Otto; Jeffrey S Ross; Levi Garraway; Vincent A Miller; Phillip J Stephens; Garrett M Frampton Journal: Genome Med Date: 2017-04-19 Impact factor: 11.117
Authors: Clinton L Cario; Emmalyn Chen; Lancelote Leong; Nima C Emami; Karen Lopez; Imelda Tenggara; Jeffry P Simko; Terence W Friedlander; Patricia S Li; Pamela L Paris; Peter R Carroll; John S Witte Journal: BMC Cancer Date: 2020-08-28 Impact factor: 4.430